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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Dysfunctional pancreatic cells differentiated from induced pluripotent stem cells with mitochondrial DNA mutations

  • So, Seongjun (Department of Convergence Medicine & Stem Cell Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Lee, Song (Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Lee, Yeonmi (Department of Biomedical Science, College of Life Science and Center for Embryo & Stem Cell Research, CHA Advanced Research Institute, CHA University) ;
  • Han, Jongsuk (Department of Biomedical Science, College of Life Science and Center for Embryo & Stem Cell Research, CHA Advanced Research Institute, CHA University) ;
  • Kang, Soonsuk (Department of Biomedical Science, College of Life Science and Center for Embryo & Stem Cell Research, CHA Advanced Research Institute, CHA University) ;
  • Choi, Jiwan (Department of Biomedical Science, College of Life Science and Center for Embryo & Stem Cell Research, CHA Advanced Research Institute, CHA University) ;
  • Kim, Bitnara (Department of Biomedical Science, College of Life Science and Center for Embryo & Stem Cell Research, CHA Advanced Research Institute, CHA University) ;
  • Kim, Deokhoon (Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Yoo, Hyun-Ju (Department of Convergence Medicine & Stem Cell Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Shim, In-Kyong (Department of Convergence Medicine & Stem Cell Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Oh, Ju-Yun (Department of Convergence Medicine & Stem Cell Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Lee, Yu-Na (Department of Convergence Medicine & Stem Cell Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Kim, Song-Cheol (Department of Convergence Medicine & Stem Cell Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Kang, Eunju (Department of Biomedical Science, College of Life Science and Center for Embryo & Stem Cell Research, CHA Advanced Research Institute, CHA University)
  • Received : 2022.02.10
  • Accepted : 2022.05.04
  • Published : 2022.09.30
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Abstract

Diabetes mellitus (DM) is a serious disease in which blood sugar levels rise abnormally because of failed insulin production or decreased insulin sensitivity. Although many studies are being conducted for the treatment or early diagnosis of DM, it is not fully understood how mitochondrial genome (mtDNA) abnormalities appear in patients with DM. Here, we induced iPSCs from fibroblasts, PBMCs, or pancreatic cells of three patients with type 2 DM (T2D) and three patients with non-diabetes counterpart. The mtDNA mutations were detected randomly without any tendency among tissues or patients. In T2D patients, 62% (21/34) of iPSC clones harbored multiple mtDNA mutations, of which 37% were homoplasmy at the 100% mutation level compared to only 8% in non-diabetes. We next selected iPSC clones that were a wild type or carried mutations and differentiated into pancreatic cells. Oxygen consumption rates were significantly lower in cells carrying mutant mtDNA. Additionally, the mutant cells exhibited decreased production of insulin and reduced secretion of insulin in response to glucose. Overall, the results suggest that screening mtDNA mutations in iPSCs from patients with T2D is an essential step before pancreatic cell differentiation for disease modeling or autologous cell therapy.

Keywords

Acknowledgement

The study was supported by grants from the National Research Foundation of Korea (NRF-2015K1A4A3046807, NRF-2019M3A9H110358211, and NRF-2020M3A9E4036527), Asan Institute for Life Sciences, Korea (2020IP0021 and 2021P0018-1), Ministry of Health and Welfare of Korea (HI16C1559) and Ministry of Trade, Industry & Energy (MOTIE, Korea, Alchemist Project 20012378).

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